A systematic review of case series and clinical trials investigating systemic oral or injectable therapies for the treatment of vitiligo

Abstract Aims and objectives The purpose of this study is to investigate the effectiveness and safety of oral and injectable systemic treatments, such as methotrexate, azathioprine, cyclosporine, tofacitinib, baricitinib, corticosteroids, statins, zinc, apremilast, etc., for treating vitiligo lesions. Method Databases including PubMed, Scopus, and Web of Science were meticulously searched for studies spanning from 2010 to August 2023, focusing on systemic oral and injectable therapies for vitiligo, using comprehensive keywords and search syntaxes tailored to each database. Key data extracted included study design, treatment efficacy, patient outcomes, patient satisfaction, and safety profiles. Results In a total of 42 included studies, oral mini‐pulse corticosteroid therapy (OMP) was the subject of six studies (14.2%). Minocycline was the focus of five studies (11.9%), while methotrexate, apremilast, and tofacitinib each were examined in four studies (9.5%). Antioxidants and Afamelanotide were the subjects of three studies each (7.1%). Cyclosporine, simvastatin, oral zinc, oral corticosteroids (excluding OMP) and injections, and baricitinib were each explored in two studies (4.8%). Azathioprine, mycophenolate mofetil, and Alefacept were the subjects of one study each (2.4%). Conclusion Systemic treatments for vitiligo have been successful in controlling lesions without notable side effects. OMP, Methotrexate, Azathioprine, Cyclosporine, Mycophenolate mofetil, Simvastatin, Apremilast, Minocycline, Afamelanotide, Tofacitinib, Baricitinib, Antioxidants, and oral/injectable corticosteroids are effective treatment methods. However, oral zinc and alefacept did not show effectiveness.


INTRODUCTION
Vitiligo is a relatively common condition that affects approximately 1% of the global population. 1 It is caused by the destruction of melanocytes, the cells responsible for producing skin pigment.This results in the appearance of white patches on the skin, which can be particularly distressing for individuals with darker skin tones. 2 While vitiligo is not a life-threatening condition, it can have a significant impact on quality of life, leading to social stigma, anxiety, and depression. 3ere are various treatment options available for vitiligo, including topical corticosteroids, phototherapy, and surgical interventions. 4,5wever, systemic oral or injectable therapies have also been investigated as potential treatments for the condition.These therapies work by targeting the immune system, which is thought to play a role in the destruction of melanocytes in vitiligo. 2Systemic treatments introduced for vitiligo include oral and intravenous corticosteroids, cyclosporine, azathioprine, methotrexate, Janus kinase pathway inhibitors, minocycline, apremilast, and others.8][9][10] The aim of this systematic review is to provide a comprehensive overview of the available evidence on systemic therapies for vitiligo.
This includes an analysis of case series and clinical trials investigating the efficacy and safety of these treatments.By synthesizing the findings of multiple studies, this review aims to provide a more robust understanding of the potential benefits and limitations of systemic therapies for vitiligo.This information can be used by clinicians and researchers to inform treatment decisions and guide future research in this area.

What is already known about this topic?
• Currently, the treatment options for vitiligo are determined by the size and extent of the affected areas.For smaller areas, local treatments are typically the preferred option, while larger areas may require a combination of phototherapy and local treatments.• There have been recent reports of effective treatment for large areas of vitiligo using systemic treatments, such as oral or injectable medications.The JAK inhibitor family, phosphodiesterase inhibitors (including apremilast), minocycline, methotrexate, and corticosteroids have shown promising results.This type of treatment is typically recommended when the affected areas are too large for topical treatments and phototherapy is not feasible for the patient due to various reasons.

What does this study add?
• This study systematically reviewed 1275 articles related to systemic treatment of vitiligo and finally included 42 articles in the study.A total of 2413 patients participated in these studies, with 609 being women, 711 being men, and 1113 having an unknown gender.The effectiveness of the injectable form of the drug has been investigated in six studies, while 37 studies have investigated the effectiveness of the oral form of the drug.Furthermore, the majority of the patients included in our study exhibited non-segmental generalized vitiligo.
• Oral mini-pulse corticosteroid therapy (oral dexamethasone and low-dose oral prednisolone) has been the most commonly used modality in studies.The highest rate of recovery with this modality was the incidence of repigmentation in all patients within 16.1 weeks.Additionally, repigmentation occurred in 91.8% of patients within 13.2 weeks.
• The results of our study have shown that oral zinc (2 studies) and injection alefacept (1 study) do not have a significant effect on improving vitiligo.

Inclusion and exclusion criteria
The inclusion criteria encompassed studies involving patients diagnosed with vitiligo, regardless of age, gender, or ethnicity, and focusing on systemic or injectable treatments, including methotrexate, azathioprine, cyclosporine, tofacitinib, baricitinib, corticosteroids, statins, zinc, apremilast, and similar agents.Only studies that provided clear outcomes on vitiligo lesion treatment were considered.Exclusion criteria included studies that were not case series or clinical trials, those focusing on topical or non-systemic treatments such as regenerative medicine, or using systemic treatments in combination with other types of treatments, non-human studies (including animal studies and laboratory studies), and studies without clear outcome measures.
Studies not published in English or those without accessible full-text versions were also excluded.

Study selection and data extraction
Two reviewers [A.J. and S.A] evaluated the titles and abstracts of the retrieved records according to the eligibility criteria.The studies were analyzed for various characteristics, including study design, treatment method, follow-up intervals, and criteria for evaluating improvement.
Participant characteristics, such as mean age, gender ratio, and sample size, were extracted from the records.The results of the studies, detailing aspects such as lesion healing, patient satisfaction, adverse effects, and safety, were also extracted.EndNote® X8 and Google Sheets™ were utilized to screen the articles and extract pertinent data.Two researchers independently conducted the screening and data collection, and any disagreements were resolved through consultation with a more experienced researcher [A.G.].

Literature search
screening the remaining articles based on their titles and abstracts, 789 articles were excluded.Finally, a total of 42 articles were selected for data extraction and included in the qualitative synthesis (Figure 1).

Study characteristics
Included studies were published between 2010 and 2023.Most included studies were clinical trials (81.3%), case series (4.6%) and pilot studies (13.9%) containing data specific to systemic treatment for vitiligo, including 18 different systemic treatments.The study included a total of 2,413 patients, of whom 609 (25.3%) were women and 711 (29.5%) were men.Gender was not clearly defined in 1,113 patients (46.2%).adult populations were mostly represented in the included studies (Table 2).All studies included in the systematic review were qualitatively assessed to minimize the risk of bias; included studies were deemed to be of acceptable quality.
The aim of this systematic review is to summarize the current literature on systemic oral or injectable therapies for the treatment of vitiligo, as well as to investigate their potential side effects.
Out of a total of 42 studies included, six studies(14.2%)were related to the effectiveness of oral mini-pulse corticosteroid therapy(OMP), five studies(11.9%)were related to minocycline, four studies(9.5%)were related to methotrexate, four studies(9.5%)were related to apremilast, four studies(9.5%)were related to tofacitinib, three studies(7.1%)were related to antioxidants, three studies(

OMP (oral mini-pulse therapy)
Six studies with eight intervention groups investigated the effectiveness of OMP.A total of 161 patients received OMP treatment, and seven groups (87.5%) showed significant improvement, with 146 patients (90.6%) experiencing positive results.
Several studies have been conducted to assess the effectiveness of OMP in treating vitiligo and compare it with other treatments.One such study involved 444 vitiligo patients who were given oral dexamethasone as a monotherapy, with a dosage of 2.5 mg per day for two consecutive days.The study found that after 13.2 ± 3.1 weeks, disease activity was arrested in 91.8% of the patients, and all patients experienced repigmentation of their lesions after a mean of 16.1 ± 5.9 weeks. 11OMP was found to be a successful treatment, however, some patients experienced adverse effects such as weight gain, feeling sluggish, and developing acne-like skin eruptions.[13][14] On the other hand, low-dose oral prednisolone (0.3 mg/kg/day) was found to be associated with even more adverse effects than oral dexamethasone pulse therapy in treating vitiligo. 2Three clinical trial studies were conducted to compare the effectiveness of oral mini-pulse dexamethasone and NB-UVB phototherapy in treating vitiligo.
One of the studies found that combining NB-UVB phototherapy with oral prednisone (30 mg/day on two successive days every week for 3 months) resulted in a statistically significant reduction in VASI score, compared to NB-UVB phototherapy alone.However, treatment with steroids alone did not show a significant decrease in VASI scores for vitiligo patients. 5In a study, it was found that the time it took for vitiligo lesions to stop spreading was slightly shorter in patients who received a combination of OMP (4 mg dexamethasone on two consecutive days per week), NB-UVB, and clobetasol cream 0.05%, compared to those who only received NB-UVB and topical clobetasol.Both groups experienced a reduction in the amount of skin affected by vitiligo. 1A study showed that when OMP (at a dose of 0.5 mg/kg on two consecutive days per week) was combined with NB-UVB, around 59.4% of cases showed a moderate level of repigmentation within the first 3 months of treatment. 12

Azathioprine
The effectiveness of azathioprine in treating vitiligo was investigated in an intervention group consisting of 27 patients, and a significant improvement in the lesions was observed.
A study found that using Azathioprine at a dose of 50 mg twice daily for 10 months was not as effective as using OMP (a tablet containing betamethasone at a dose of 5 mg, taken as a single dose on two consecutive days every week) in stopping the progression of the condition and inducing repigmentation.However, Azathioprine had a better side effect profile.One patient who used Azathioprine reported experiencing pancreatitis.In the first month, the average number of lesions was 2.6, while in the tenth month, it decreased to 0.52. 7

Cyclosporine
Two studies, involving a total of 33 patients, evaluated the effectiveness of Cyclosporine in treating the condition.The results of both studies confirmed a significant improvement.
Using oral cyclosporine at a dose of 3 mg/kg/day halted the progression of vitiligo in 61% of the patients.It was interesting to note that 81% of these also showed re-pigmentation. 6comparison was made between the effectiveness of OMP (2.5 mg betamethasone per day on two consecutive days) for 4 months and cyclosporine (3 mg/kg/day) for 4 months in treating a certain condition.The study found that there was no significant difference in the Arrest of disease progression (ADP) after 6 months between the two groups.The group that received cyclosporine had a percentage of 88%.However, the mean time taken to achieve ADP was significantly lower in the cyclosporine group compared to the OMP group.The study also reported several adverse reactions of cyclosporine, including paresthesia, gingival hyperplasia, myalgia, hypertension, headache, hyperuricemia, hypertrichosis, hyperbilirubinemia, and dyspepsia.

Methotrexate
Out of the four studies with five intervention groups that examined the effectiveness of methotrexate in treating vitiligo, three studies (75%) with four intervention groups (80%) demonstrated its significant effectiveness in treating vitiligo lesions.A total of 98 patients participated in these studies.
One study showed no improvement in lesions after 6 months of treatment with a dose of 25 mg/week of MTX.Another study showed a significant improvement in the group treated with MTX with a dose of 10 mg per week, although this improvement was not significantly different from the group treated with OMP (2.5 mg betamethasone taken on two consecutive days per week).Out of 25 patients, only six showed the spread of lesions during the 24 weeks of treatment.MTX caused severe nausea. 3,16A different research study found that taking oral MTX (15 mg split into three doses, taken every 12 hours, once a week for 3 months) along with 2.5 mg tablets of folic acid, and also taking OMP dexamethasone 5 mg/day for two days every week for 3 months, resulted in a significant decrease in the spread of the disease compared to taking each of these medications alone. 17Using a combination of 10 mg MTX once and NB-UVB for 4 months resulted in superior outcomes compared to using only NB-UVB treatment.Additionally, there were no reported adverse effects associated with this combined therapy.Indeed, in the group that received methotrexate in addition to NB-UVB, the reduction in repigmentation was 18.41%, whereas, in the group that received only NB-UVB, this reduction was 9.21%. 18

Apremilast
Out of four studies (with four intervention groups) investigating the effectiveness of apremilast in the treatment of vitiligo, three studies (75%) confirmed its significant effectiveness.A total of 122 patients participated in these studies.
A study involving 40 cases of individuals with both vitiligo and psoriasis found that nine of them experienced partial repigmentation with the use of apremilast.The improvement was first observed in the most recent vitiligo lesions on the lower face and neck, while the extremities did not respond to the treatment. 10The addition of apremilast therapy resulted in a shorter time for repigmentation compared to standard treatment alone.However, there were no significant differences in the VASI score (vitiligo area scoring index) when apremilast was added to the regimen.The time interval between the start of apremilast and the beginning of repigmentation was reported to be 4 weeks, and the reduction of Vitiligo Area Scoring Index (VASI) was 1.24.In the control group, the beginning of repigmentation was reported after 7 weeks, and the reduction of VASI was reported to be 0.05. 19When comparing NB-UVB therapy alone to the combination of NB-UVB and Apremilast therapy, there were no significant differences found in the VASI score, Dermatology Life Quality Index, and visual analog scale scores. 20The findings showed that the combination of apremilast and NB-UVB phototherapy was more effective in promoting repigmentation of generalized vitiligo and faster than using NB-UVB or apremilast alone. 21

Minocycline
Minocycline's effectiveness in treating vitiligo has been investigated in five studies, with five intervention groups, and in all five studies (100%), it has shown significant effectiveness in treating vitiligo.A total of 93 patients participated in these studies.
The administration of minocycline at a dosage of 100 mg once daily for a period of 3 months has been found to halt the progression of the disease. 9en comparing the effectiveness of minocycline (100 mg/day) and prednisolone (administered orally at a dosage of 0.3 mg/kg/day for 2 months, followed by 0.15 mg/kg/day in the third month) in controlling vitiligo activity, it was found that 100% of patients in the minocycline group showed control of the disease, compared to 60% in the prednisolone group.The VIDA score was used to compare the two groups, and while both showed a statistically significant difference, the minocycline group showed a greater reduction, indicating that minocycline was more effective in controlling vitiligo activity. 22ere was no statistically significant difference between the average VIDA scores of patients who received minocycline 100 mg/day and those who received OMP 2.5 mg.However, patients who received OMP reported experiencing more side effects. 23o randomized clinical trials were conducted to compare the effects of minocycline and NB-UVB on vitiligo treatment.In the first study, 76.1% of patients with disease in the NB-UVB group achieved stability, while only 33.3% of patients in the minocycline group achieved stability.The NB-UVB group also showed statistically significant changes in diameter at the end of treatment compared to the minocycline group.Side effects were reported by 14.2% of minocycline users, including oral mucosal pigmentation, gastrointestinal complaints, and headaches. 24However, the other study demonstrated that the combination of minocycline and NB-UVB was slightly more effective than NB-UVB alone, with a higher percentage improvement in VASI scores compared to the monotherapy group. 25

Oral zinc
Two clinical trials were conducted to investigate the effect of zinc on vitiligo, and both studies (100%) showed that adding oral zinc (220 mg per capsule, twice daily) did not result in a significant improvement in the disease outcome. 4,26A total of 62 patients underwent intervention by receiving zinc capsules across these two studies.

Simvastatin
Two studies have investigated the effectiveness of simvastatin in treating vitiligo, and one study (50%) has shown significant effectiveness of this drug.A total of 102 patients participated in these studies.
A study demonstrated that administering Simvastatin at a dosage of 80 mg/day resulted in an improvement of the lipid profile and a reduction in vitiligo disease activity.This suggests that Simvastatin could be a beneficial treatment option for individuals with both vitiligo and dyslipidemia. 27Conversely, another study found that administering Simvastatin at a dosage of 80 mg/day did not demonstrate a statistically significant improvement compared to conventional treatment for vitiligo.The study concluded that oral Simvastatin did not have a significant impact on the treatment of vitiligo. 28

Afamelanotide
Three studies were conducted to investigate the impact of afamelanotide and compare it with NB-UVB phototherapy.0][31] A total of 153 patients were involved in these studies, and no adverse effects of either afamelanotide or NB-UVB were reported in any of these studies.

Tofacitinib
Four studies involving 38 patients have been conducted to evaluate the effectiveness of tofacitinib on vitiligo.Among these studies, three (75%) have demonstrated the significant effectiveness of this drug in treating vitiligo.
In a study, it was found that only 50% of the patients experienced a 5.4% decrease in the affected body surface area (BSA) caused by vitiligo in sun-exposed areas, while the remaining half did not observe any improvement in skin pigmentation.The study also revealed some adverse effects, including upper respiratory tract infection, weight gain, joint pain, and abnormal lipid profile, linked to the usage of tofacitinib. 32In another study, the reported side effects were pain in the joints of the hands and feet. 8Three studies were conducted to compare tofacitinib with NB-UVB and their combination therapy.In two of the studies, the combination of tofacitinib and NB-UVB showed better results in terms of repigmentation rate compared to NB-UVB monotherapy.Therefore, adding tofacitinib to phototherapy resulted in better outcomes.The results of this study show a repigmentation rate of 92% in the group receiving phototherapy and tofacitinib, compared to a repigmentation rate of 77% in the group receiving phototherapy alone. 8,33In contrast, the third study suggested that the combination of 5 mg daily tofacitinib with NB-UVB phototherapy for 16 weeks is not effective in treating patients who did not respond well to previous treatments. 34

Baricitinib
In two studies, the effectiveness of baricitinib in treating vitiligo was investigated, and both studies showed a significant recovery of the lesion (100%).A total of 12 patients participated in these studies.The first study demonstrated that baricitinib was both effective and safe in treating progressing vitiligo (with a significance level of p < 0.05). 35 a study involving eight vitiligo patients, baricitinib was administered and their progress was monitored at 3 and 6 months.The study found that after 3 and 6 months of treatment, the significant efficiency was 35.3% and 55.9%, respectively, and the total effective rate was 67.6% and 73.5%, respectively.However, after 6 months of treatment, the effectiveness on extremities was lower than that on the trunk and limbs.Overall, the study concluded that baricitinib is a safe and effective treatment for progressive vitiligo (p < 0.05), but its effectiveness is influenced by the duration of treatment and the location of the lesions. 36

Anti-oxidant
Three studies, involving a total of 131 patients, investigated the effectiveness of antioxidants in treating vitiligo.Out of these, two studies (66.6%) have demonstrated the effectiveness of antioxidants in treating vitiligo.
Taking an oral supplement three times a day for 6 months, which contained P. emblica (100 mg), vitamin E (4.7 mg), and carotenoids (10 mg) as an antioxidant, resulted in mild repigmentation on the head/neck regions (p = 0.019) and a trend toward repigmentation on trunk (p = 0.051).However, using the antioxidant showed a higher percentage of stable disease (p = 0.065). 37Administering oral 8-methoxypsoralen on three alternate days per week at a dose of 0.6 mg/kg body weight, in addition to standard treatment, did not show a statistically significant difference compared to standard therapy alone (p = 0.052). 38In another study, the most significant improvement in the repigmentation of skin lesions was observed in patients who received a combined therapy of oral antioxidant supplementation (vitamin A + E) at a dose of 5000 IU of retinol and 400 mg of tocopherol, along with phototherapy. 39

Alefacept injection
A pilot study involving four patients was conducted to assess the safety and efficacy of alefacept in treating vitiligo.The study found that all patients tolerated alefacept well and did not experience any adverse events.However, none of the patients showed any repigmentation (0%) when treated with alefacept as a monotherapy for vitiligo, indicating that it did not result in any improvement. 40

Using corticosteroids for treatment, except OMP
Both of the two studies that investigated the effectiveness of oral (except OMP) and injection of corticosteroids showed significant improvement in vitiligo lesions.A total of 305 patients participated in these two studies.
The average VIDA was significantly reduced after a three-day treatment of 500 mg of intravenous methylprednisolone taken once daily. 41 a clinical study, 272 patients were divided into three groups: one group received oral prednisone along with topical glucocorticoid, while the other two groups received compound betamethasone injection along with topical glucocorticoid.These latter two groups were referred to as the systemic and topical glucocorticoid groups.After 3 months, the rate of expansion of skin lesion area was significantly lower in the oral prednisone + topical glucocorticoid group and the compound betamethasone injection + topical glucocorticoid group compared to the topical glucocorticoid group. 42

DISCUSSION
Treatment of vitiligo, an autoimmune disease that results in adverse manifestations on a person's skin, is crucial.Our initial step in dealing with patients with limited lesions involves the use of topical treatments, including topical corticosteroids and topical calcineurin inhibitors. 26However, in cases of extensive lesions or those resistant to local treatment, we must resort to systemic treatment or phototherapy. 24It's important to note that due to the need for patients to frequently visit the clinic for phototherapy, which may interfere with their work and education, opting for systemic treatment becomes an acceptable option for them.In this section, we will discuss the findings of our systematic study on systemic treatments for vitiligo.
The first systemic treatment discussed is oral mini-pulse corticosteroid, whose effective results are discussed in the results section. 7,13lse therapy generally refers to the administration of drugs at a higher dose than the pharmacological dose in an alternating manner.The aim of this therapeutic method is to achieve high efficacy with minimal side effects. 43The investigation of OMP in the treatment of vitiligo was initially conducted by Pasricha et al., 44 and their findings showed favorable treatment outcomes.The dose used in Pasricha's study was two tablets of 5 mg betamethasone on two consecutive days per week.In the studies reviewed by us, the effectiveness of oral corticosteroids in treating vitiligo has been demonstrated, either as monotherapy or in combination with other systemic treatments or phototherapy. 12,23e studies reviewed by us involved various doses, such as 2.5 mg of dexamethasone daily on two consecutive days per week, a dose of 0.3 mg/kg of prednisolone, 30 mg of oral prednisolone per day for two consecutive days per week, 4 mg of dexamethasone daily on two consecutive days per week, and 0.5 mg/kg of prednisolone on two consecutive days per week.All of these doses were found to be significantly effective. 2,5,11athioprine, derived from 6-mercaptopurine, is a synthetic purine analog.It acts as a purine antagonist, and its active metabolites work by interfering with the normal function of naturally occurring purines in the body.As a result, it exhibits both cytotoxic and immunosuppressive effects. 45According to the mentioned mechanism, this drug can be effective in treating autoimmune diseases and vitiligo.Our review has demonstrated its significant effectiveness, although the effectiveness rate was found to be lower compared to mini-pulse therapy with betamethasone.However, considering its fewer side effects in comparison to betamethasone, it can still be considered as a suitable treatment option 7 .
Another immunosuppressive drug that has proven effective in the treatment of vitiligo in our systemic study is cyclosporine.Cyclosporine is a calcineurin inhibitor with selective action on T cells.Since 1997, it has been used in dermatology specifically for its US Food and Drug Administration-approved indication for psoriasis.Additionally, it has been utilized off-label for the treatment of various inflammatory skin conditions, such as atopic dermatitis, blistering disorders, and connective tissue diseases.This drug has demonstrated efficacy in managing these conditions and has become a valuable option in the field of dermatology. 46The dose used in the studies we reviewed was 3 mg/kg/day, which was proven to be significantly superior to OMP therapy in one study.However, it is important to also consider the potential side effects of this drug. 6,13e next immunosuppressive drug that has shown significant effects in the treatment of vitiligo is mycophenolate mofetil.Mycophenolate mofetil works by blocking the activity of inosine-5′ monophos-phate dehydrogenase, an enzyme involved in the production of new purines within T and B lymphocytes.By doing so, it specifically targets and impacts lymphocytes throughout the complete range of immune cells.The prescribed dose in the study reviewed by us was 2 grams daily for 6 months.Compared mini-pulse corticosteroids of equal effectiveness, the duration of stopping the progress of the lesions is longer, and the probability of recurrence is higher after stopping the drug.At the same time, it has fewer side effects than corticosteroids and can be a suitable treatment option in cases where we have to stop corticosteroids due to side effects. 14,15 also studied methotrexate as an immunosuppressive drug.In autoimmune disease, methotrexate can prevent certain immune cells from functioning properly, including neutrophils and monocytes.It can also inhibit the movement of certain immune cells and prevent them from releasing certain cytokines, such as TNF-α, IL-6, IL-10, and IL-12.Additionally, methotrexate can selectively cause the death of activated, rapidly dividing CD4 T cells, while leaving resting T cells unharmed. 3The results of one of our studies have shown the ineffectiveness of methotrexate with a dose of 25 mg per week in the treatment of vitiligo lesions. 47While another study has reported the significant effectiveness of methotrexate with a dose of 10 mg per week for vitiligo, and of course, it has not reported a significant difference in the comparison of the improvement rate of corticosteroid OMP and methotrexate. 3Our third study also confirmed the effectiveness of methotrexate with a dose of 15 mg per week.The fourth study also confirmed that the addition of methotrexate to NB-UVB causes a significant difference in recovery compared to phototherapy alone. 18According to the results of most of the reviewed studies, it seems that treatment with methotrexate is effective for patients.
Apremilast is an inhibitor of phosphodiesterase 4 (PDE4), which plays a role in regulating cyclic nucleotides in the body.Inflammatory cells are particularly sensitive to changes in cyclic nucleotides, and by inhibiting PDEs, apremilast can significantly increase intracellular cAMP levels, resulting in a variety of anti-inflammatory effects.
This medication has received approval for treating adult patients with active and moderate-to-severe chronic plaque psoriasis.Because of its ability to regulate the immune system and its positive safety record, apremilast is currently being studied as a potential treatment choice for various other inflammatory disorders. 10,48In three out of the four studies we reviewed, the effectiveness of apremilast in treating vitiligo was confirmed, and no specific side effects were reported. 10,19,21It is anticipated that this drug will become a widely used treatment option for vitiligo in the future.
Minocycline is an antibiotic that also has antioxidant properties, which can help reduce the harmful effects of oxidative stress on the nervous system.This suggests that minocycline could potentially be used as a preventive measure to protect melanocytes from damage and loss during the early stages of vitiligo. 93][24][25] However, in one study, no significant difference was observed between the group receiving minocycline and the group receiving OMP. 23In another study, its effectiveness was reported to be less than phototherapy. 24The variable therapeutic response of this drug compared to other treatment methods may be related to its greater effectiveness in the early stages of vitiligo, where it can prevent further destruction of melanocytes.
Zinc is a crucial trace element that has a significant impact on overall health and disease prevention.When combined with other micronutrients, it plays a vital role in the melanogenesis process and helps prevent the destruction of melanocytes due to its antioxidant properties.However, after reviewing several studies, we found that adding zinc to the treatment regimen of vitiligo patients did not result in a clinical response. 4,26This could be explained in two ways: first, zinc may only be effective in treating vitiligo when it is absent from the blood, and second, early initiation of zinc treatment may help prevent the development and destruction of melanocytes. 49,50 the last 20 years, studies have been started to explore the potential of using statins for treating dermatologic disorders, based on the suggested primary immunomodulatory function of these medications. 51,52One of the two studies that were examined showed that simvastatin was effective, 27 while the other study did not show any significant improvement. 28Based on these findings, it cannot be denied that the drug is effective, but it may be a good treatment option for patients who have high cholesterol levels or are at risk of cardiovascular events.
Afamelanotide is a controlled-release synthetic analog of α-MSH, which is naturally occurring.Research has indicated that patients with vitiligo have issues with their melanocortin system.Therefore, it is believed that using external melanocortin peptides to restore the system could potentially help these patients. 29,300][31] The addition of afamelanotide to NB-UVB was found to stimulate the differentiation and proliferation of melanoblasts. 30e drug Tofacitinib, which is an inhibitor of Janus kinase 1/3 (JAK), is believed to have an impact on vitiligo lesions by blocking the signaling of interferon-gamma (IFN-γ) in the skin. 53Tofacitinib is a medication that has multiple applications in the treatment of inflammatory skin conditions such as psoriasis, alopecia areata, lichen planus, and vitiligo.
Its uses are expanding continuously, 54 herefore, we conducted a study to evaluate its efficacy in treating vitiligo, and the results are presented in the "Results" section.The study demonstrated that tofacitinib is effective in treating vitiligo, and it can be used alone or in combination with other therapies.
Baricitinib is a type of small-molecule inhibitor that can reversibly compete with the Janus kinase (JAK) family.Its primary action is on the JAK1 and JAK2 subtypes, and it has a lower potency against other subtypes.In dermatology, baricitinib has gained popularity as a novel molecular-targeted therapy.Several studies have shown that baricitinib is effective in treating various skin conditions such as atopic dermatitis (AD), alopecia areata (AA), psoriasis, and vitiligo. 55The results of our study have also shown the significant effectiveness of this drug in treating vitiligo. 56ntioxidants are another effective treatment for vitiligo.In recent times, there has been an increasing interest in examining the impact of oxidative stress in vitiligo by exploring different antioxidant markers.Numerous theories have been put forward, including the autocytotoxic-metabolic theory, which suggests that oxidative stress plays a key role in the disappearance of melanocytes.[59] The results of our study have demonstrated the effectiveness of antioxidants in treating vitiligo, as evidenced by the majority of studies.Significant improvements in vitiligo recovery have been observed with the combination of vitamin E, carotenoids, and P. emblica. 37Additionally, the combination of vitamin A and E has been associated with significant improvement in vitiligo lesions. 39Vitamin E has been indicated for the treatment of various skin diseases, including Yellow nail syndrome, Subcorneal pustular dermatoses, Cutaneous amyloidosis, Atopic dermatitis, and Hailey-Hailey disease. 60The treatment of vitiligo can also be added to this list of indications.Phyllanthus emblica, as a plant, possesses anti-inflammatory, anti-cancer, and antioxidant effects, and can be used as a complementary treatment in the management of vitiligo. 61efacept is a type of artificial protein that is made up of two parts-the part of LFA-3 that binds to CD2 on T lymphocytes, and a portion of human IgG1.When alefacept attaches to CD2 on memoryeffector T lymphocytes, it prevents their activation and decreases their quantity. 62Although Alefacept suppresses lymphocytes, it was anticipated to improve vitiligo to some extent, similar to other immunosuppressive drugs.However, the results of the only pilot study conducted in this regard have been disappointing, with no significant improvement observed.It should be noted that the sample size of this study was only four people, and the effectiveness of this drug cannot be conclusively rejected.This is especially true given reports of the drug's good tolerance and the absence of side effects. 63rticosteroids prevent the development and spread of vitiligo lesions by suppressing antibody production, inducing apoptosis of cytotoxic T cells, and causing repigmentation of the affected area.In our study, significant effectiveness has been associated with intravenous pulses of methylprednisolone, daily oral treatment with prednisone and prednisolone, as well as betamethasone injection. 41

CONCLUSION
We conclude that systemic treatments play a significant role in controlling vitiligo lesions, and no serious side effects have been reported in any of the treatment methods.Treatment methods such as OMP, Methotrexate, Azathioprine, Cyclosporine, Mycophenolate mofetil, Simvastatin, Apremilast, Minocycline, Afamelanotide, Tofacitinib, Baricitinib, Antioxidants, and oral and injectable forms of corticosteroids have always been accompanied by reports of therapeutic success.However, oral zinc and alefacept were not effective in any of the intervention groups.The limitation of our study is the small number of clinical trials and case series investigating some treatment methods, and in some studies, the sample size was small.We suggest that more extensive clinical studies with larger sample sizes be conducted in the future to reach a more comprehensive conclusion regarding the effectiveness of systemic treatments in vitiligo.

Age group of patients with vitiligo Younger than 20 years of age.
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TA B L E 3 A summary of reviewed literature. Author, year Design of study Study sample Age (mean) Sex ratio(F:M) Intervention method Effectiveness Adverse events
24:18The participants were divided equally into two groups: the NB-UVB group and the minocycline group.The NB-UVB group received phototherapy twice a week on non-consecutive days.On the other hand, the minocycline group was instructed to take a daily dosage of 100 mg of minocycline.Both groups underwent treatment for a period of 3 months.

Design of study Study sample Age (mean) Sex ratio(F:M) Intervention method Effectiveness Adverse events
• .In the second group, the treatment consisted of a topical corticosteroid, which was compatible with the one used in the first group.However, in addition to the corticosteroid, they also administered oral zinc sulfate, specifically two 220-mg capsules 9:5 In the first group, there were seven vitiligo patients who received a combined treatment of minocycline at a daily dose of 100 mg along with NB-UVB.In the second group, there were also seven patients who received a placebo in addition to NB-UVB.TA B L E 3 (Continued)Author,

year Design of study Study sample Age (mean) Sex ratio(F:M) Intervention method Effectiveness Adverse events
UnknownUnknown Group 1 was given betamethasone OMP, which consisted of a 5 mg tablet of betamethasone.This tablet was administered as a single dose on two consecutive days, repeated every week.On the other hand, Group 2 was administered a tablet of azathioprine, with a dosage of 50 mg, twice daily, for a duration of 6 months.